Method of decarbonylation

ABSTRACT

DI- AND TRI-SUBSTITUTED PYRROLES MAY BE PREPARED B Y DECARBONYLATING OF THE CORRESPONDING MONO- AND DI-CARBOXYLIC ACID ESTERS AND MONO- AND DI-KETONES BY WARMING THE ESTERS OF KETONES WITH PHOSPHORIC ACID.

United States Patent O US. Cl. 260-313.1 14 Claims ABSTRACT OF THEDISCLOSURE Diand tri-substituted pyrroles may be prepared bydecarbonylating of the corresponding monoand di-carboxylic acid estersand monoand di-ketones by warming the esters of ketones with phosphoricacid.

RELATED APPLICATIONS This application is a continuation-in-part of ourcopending application Ser. No. 468,633 filed June 30, 1965, nowabandoned.

FIELD OF THE INVENTION A novel method of decarbonylation carboxylic acidesters and ketones of pyrroles.

DESCRIPTION OF THE PRIOR ART Heretofore it has been known todecarboxylate the carboxylic acid esters of diand tri-substitutedpyrroles particularly C-substituted pyrroles. However these methods havebeen substantially unfeasible for commercial application. In theprincipal method known to the art, the esters are hydrolyzed anddecarboxylated to the tri-substituted pyrroles of Formula A by heatingwith strong sulfuric acid (3 vols. conc. H SO +1 vol. H O) on a steam 40bath until the evolution of CO and the alcohol, e.g., C H OH when R is CH is completed. In general, this step takes from one to one and one-halfhours. (See Formulas I to V1 in column -3).

Since the tri-substituted pyrroles and even more so di-substitutedpyrroles, are sensitive to oxygen and hot acids, it is customary tocarry out the hydrolysis and decarboxylation in an atmosphere ofnitrogen or other inert gas. However, even under the most carefulworking conditions, the yields of the tri-substituted pyrroles in mostcases are unsatisfactory. In general, they are less than 50% of theory.The pyrrole is always accompanied by a large amount of resinousby-products (black or red tars) which, in many cases, form the mainproduct of the reaction.

We have found that the formation of these tars is due to the oxidationof the substituted pyrroles which occurs, even in the absence of oxygen,by the oxidative action of the hot sulfuric acid used in the process.Indeed, in working up the reaction mixtures, we have always observed astrong odor of S0 which results from the oxidative action of the H 80the latter being reduced in the process.

We have now made the surprising discovery that the formation of the tarscan be completely suppressed by eliminating the sulfuric acid and usingphosphoric acid (concentration of 60% to 100%) in place thereof. Thephosphoric acid of commerce has proved to be an excellent replacementfor the sulfuric acid. The phosphoric acid is not only devoid ofoxidative action but has the added advantages that the decarboxylationof the esters of Formulae IX and XI occurs at much lower temperaturesand at a much faster rate than decarboxylations effected with sulfuricacid. Thus, when using sulfuric acid, temperatures of l20 C. and timeintervals of one to one and one-half hours are required for completionof the reaction. In contrast thereto, decarboxylations with 85%phosphoric acid usually occur at 65-80 C.; and in most instances, arecompleted in ten to fifteen minutes.

It was found by Treibs and Schmidt [Ann. 577, (1952)] that carboxylicacid esters of pyrroles may be readily decarboxylated by the sequentialsteps of saponifying the esters by heating with aqueous sodium hydroxidefor several hours followed by acidification with acetic acid. It will bereadily seen that the process of the present invention which can becarried out in one step in a shorter period of time constitutes a farmore commercially viable process than that disclosed by Treibs.

Moreover, attempts were made to carry out the decarboxylation of thecarboxylic acid esters by heating the esters under reflux with glacialacetic acid. It was found that such treatment caused no change in theester whatsoever and the decarboxylation was not observed.

SUMMARY OF THE INVENTION In the process of the present invention,pyrroles of Formula A are obtained in a high state of purity and inyields of over 80% of pure product in most cases, by the phosphoric aciddecarbonylation of the corresponding pyrrole carboxylic acid esters ofpyrrolyl ketones.

The compounds of the present invention have the general Formula Awherein R and R may be hydrogen, lower alkyl, lower alkenyl, cycloalkylhaving a maximum of 8 carbon atoms, phenyl, halophenyl, loweralkoxyphenyl, and benzyl; R and R have the same values as R and R andmay additionally be linked together to form an alicyclic ring having amaximum of 8 carbon atoms provided that in the monocyclic system one ortwo members of the group R R R and R are hydrogen, and in the bicyclicsystem, one member of the group R and R is hydrogen.

The prefix lower alk. designates a straight or branched carbon chain of1-6 carbon atoms.

In the general process of the present invention, a pyrrole nucleushaving one or two carboxylic acid ester moieties, or keto-moietiessubstituted therein is heated with concentrated aqueous phosphoric acid.It is to be understood that they may be one or two carboxylic acidmoieties or keto-moieties attached to the pyrrole ring itself providedthat these moieties are not attached to adjacent carbon atoms. Thus, inthe monocyclic system, the carboxylic acid ester, or keto-moieties ifmonosubstituted may be at positions 2, 3, 4, or in the ring, wherebisubstituted may be at positions 2 and 4, 2 and 5 or 3 and 5, whereasin the bicyclic system, only monosubstitution at positions 2 or 3 isfeasible.

PREFERRED EMBODIMENTS In the preferred modification of the presentinvention, the starting material utilized is a pyrrole of the followingwherein n is 0, l, 2 or 3, R is OR, or R and R R R or R are lower alkyl,for example methyl, ethyl, propyl, butyl, pentyl, or hexyl; loweralkenyl such as vinyl, allyl, butenyl or hexenyl; cycloalkyl, forexample, cyclopentyl, cyclohexyl, or cyclobutyl, phenyl, halophenyl,such as fluorophenyl, bromophenyl or chlorophenyl; lower alkoxyphenyl,such as methoxy-, ethoxy-, propoxy-, or pentoxy-, phenyl or benzyl. R islower alkyl such as methyl, ethyl, propyl or butyl; phenyl; or benzyl.

The starting material is taken up in approximately ten times its weightof the phosphoric acid. It is preferred to use strong aqueous phosphoricacid of between 60 and 100% by weight, 85 commercial phosphoric acidbeing the most suitable. The mixture is heated if desired, in an inertatmosphere, preferably nitrogen at between 55 and 120 C. most suitablybetween 65 and 80 C. for from 5 to 30 minutes preferably for frombetween 10 to minutes. Where the starting material is a ketone ratherthan an ester reaction temperatures of between 130 and 145 C. arepreferred. The reaction is quenched by pouring the reaction mixture ontoice and neutralizing the resultant aqueous suspension with a base,preferably aqueous ammonia. The decarbonylated pyrrole is then isolatedsuitably by extracting the aqueous suspension with a suitablewater-immiscible organic solvent such as ether. The desired product isthen isolated from the solvent in the usual manner.

PREPARATION OF STARTING MATERIALS A general two-step method for thesynthesis of the tri-substituted pyrroles of Formula A consists in thereductive condensation of and a-OXiInlnO keetone (VII) with afi-keto-ester (VIII) which results in the formation of ester (IX) inaccordance with the following reaction A similar method of synthesis(which leads to di-substituted pyrroles) consists in the reductivecondensation of an u-oximino-B-ketoester (X) with a fi-keto-ester (VIII)with the dicarboxylic acid (XI) ester in accordance with the followingreaction scheme:

In the foregoing reaction schemes, R and R have the significance abovedefined, and R designates, conveniently, a suitable alkyl group,preferably lower alkyl, e.g., methyl, ethyl, propyl, etc., or a phenylor benzyl group.

This method is also applicable to the formation of compounds of FormulaeV and VI. Specific reference is made to the disclosure oftetrahydroindoles and cyclopentenopyrroles at Chem. Abs., vol. 29, col.4356 and vol. 30, col. 8208 and Also, to the preparation of thecorresponding cycloheptenopyrroles at vol. 54, col. 10898 STATEMENT OFUTILITY The compounds prepared by the process of the present inventionmay be converted to the corresponding pyrrol- S-ylketones which areuseful as muscle relaxants and sedatives and which may themselves beconverted into the corresponding 2-aminoethylpyrrol-3-ylketones whichare valuable as tranquilizers and anti-depressants. The processes forconverting the compounds produced by the present invention into thesedesirable compounds of pharmaeodynamic activity as well as methods ofusing them are disclosed in the application of Karl Schoen and Irwin J.Pachter Ser. No. 403,387, now US. Pat. No. 3,410,857, filed Oct. 12,1964, and the continuation application thereof Ser. No. 682,670 filedNov. 13, 1967, now abandoned.

PREPARATION 1 5 -butyl-2,4-dimethyl pyrrole A mixture of 600 ml. ofconcentrated sulfuric acid and 200 ml. of water was heated on a steambath in a nitrogen atmosphere; and 100 g. of ethyl5-butyl-2,4-dimethylpyrrole-3-carboxylate added rapidly thereto withstirring. Heating was continued until the carbon dioxide formationceased, which took about fifty minutes. The mixture was cooled, pouredon ice, neutralized with sodium bicarbonate and the black oily residuetaken up in ether. The ether solution was dried, the solvent removed andthe residue distilled. The 5-butyl-2,4-dimethylpyrrole distilled at105l14 C./17l9 mm. Yield: 30 g. (48% of theory).

PREPARATION 2 Diethyl 2,4-dimethylpyrrole-3,S-dicarboxylate 12 g. wasrefluxed in 100 ml. acetic acid for one hour, the solution poured onice, the solid which separated filtered, washed with water and dried.There was recovered 11.5 g. of unchanged starting material, M.P. 134.

The following are examples in accordance with the method of thisinvention. The temperatures are centigrade.

EXAMPLE 1 5-butyl-2,4-dimethylpyrrole EthylS-butyl-2,4-dimethylpyrrol-3-carboxylate, 100 g., and 800 ml. ofphosphoric acid were stirred and heated in a nitrogen atmosphere.Decarboxylation commenced at 65 and became quite vigorous at 75 Heatingwas continued for ten minutes at when the evolution of gas stopped. Themixture was cooled to room temperature, poured on 2 kg. of ice andneutralized with equal parts of ice and ammonia water. The 5-butyl-2,4-dimethylpyrrole separated as an almost colorless oil. It was taken up inether, dried over magnesium sulfate, the solvent removed and the residuefractionated in vacuo; 11 mm 105407"; yield, 53 g. (82% of theory).

In accordance with the above procedure but starting with ethyl5-butyl-3,4-dimethylpyrrole-2-carboxylate, and ethyl 4methyl-3-cyclopentyl-5-propylpyrrole-Z-carboxylate, there is obtained5-butyl-3,4-dimethylpyrrole and 4 methyl-3-cyclopentyl-5-propyl pyrrole.

EXAMPLE 2 -propyl-2,4-dimethylpyrrole Ethyl5-propyl-2,4-dimethylpyrrole-3-carboxylate, '150 g., was decarboxylatedin accordance with Preparation 1. 50 g. of the pyrrole, b mm 90 wasobtained (51% of theory).

When the reaction was carried out in accordance with the methoddescribed in Example 1, 93 g. of the starting ester gave a yield of 55g. of the pyrrole (90% of theory).

EXAMPLE 3 S-ethyl-2,4-dimethylpyrrole Ethyl5-ethyl-2,4-dimethylpyrrole-3-carboxylate, 100 g. and 800 ml. of 85%phosphoric acid were heated and stirred under nitrogen at 65-80".Decarboxylation was completed in ten minutes. On working up the reactionmixture there was obtained 50 g. of 5-ethyl-2,4-dimethylpyrrole (80% oftheory) 12 mm 91-92.

EXAMPLE 4 4-butyl 2,5-dimethylpyrrole This tri-substituted pyrrole wasprepared in accordance with the method of Example 1 from ethyl4-butyl-2,5-dimethyl-pyrrole-3-carboxylate. Decarboxylation began at 77and was completed in ten minutes at 82. From 190 g. of the startingester, a yield of 100 g. of the pyrrole (78% of theory) was obtained. b103".

EXAMPLE 5 4-propyl-2,S-dimethylpyrrole This tri-substituted pyrrole wasprepared in accordance with the method described in Example 1 from ethyl4- propyl-2,5-dimethylpyrrole 3 carboxylate. Decarboxylation began at 81and was completed at 84. From 125 g. of the starting ester, a yield of66 g. of the tri-substituted pyrrole (82% of theory) was obtained.

EXAMPLE 6 2-benzyl-4,S-dimethylpyrrole This tri-substituted pyrrole wasprepared in accordance with the method of Example 1 from methyl2-benzyl-4,5- dimethylpyrrole-3-carboxylate (M.P. l151l5.5). Since thesolid ester was insoluble in the phosphoric acid, the mixture had to beheated to 110-115 whereupon the ester melted and decarboxylationproceeded rapidly. After working up the reaction mixture, a solidmaterial was obtained which after repeated crystallations from 75%ethanol had a melting point of 51-51.5. From 22.6 g. of the startingester, a yield of 17 g. (99% of theory) was obtained.

EXAMPLE 7 5-propyl-2,4-dimethylpyrrole EthylS-propyl-2,4-dimethylpyrrole-3-carboxylate 100 g. was suspended in 800ml. of 60% phosphoric acid and heated with stirring in a nitrogenatmosphere. The ester liquefied at 103 and at the same time wasdecarboxylated. Heating was continued at 103-108 for 30 minutes when theevolution of carbon dioxide ceased. The solution was poured on ice,neutralized with ice cold ammonia water, the soil which separated takenup in ether, dried, and after evaporation of the solvent the residuedistilled in vacuo; 55 g. of 5-propyl-2,4-dimethylpyrrole. b mm, 85-88was obtained (84% of theory).

EXAMPLE 8 2,4-dimethyl-S-phenylpyrrole To a mixture of 85.8 g. of1-oximino-1-pheny1-2-propanone and 68.9 g. ethyl acetoacetate in 400 ml.acetic acid was added 85 g. zinc dust in small portions with stirring.The mixture became hot and the temperature rose to 70. After addition ofthe zinc, the mixture was refluxed for 45 minutes, then poured on 2 kg.ice. The

6 solid which separated was filtered, washed with water; dried andextracted with cyclohexane. After evaporating the solvent, 93 g. ethyl2,4-dimethyl-5-phenylpyrro1e-3- carboxylate M.P. 119 'was obtained.

The ester 4.5 g. was heated with 50 ml. of phosphoric acid withstirring. At about 115 the ester melted and decarboxylated within a fewminutes. The mixture was quenched in 200 g. ice. A solid separated whichwas filtered, washed with water, dried and crystallized from hexane.2,4-dimethyl-S-phenylpyrrole M.P. 74 was obtained; yield 3.2 g.=% oftheory.

EXAMPLE 9 2,4-dimethylpyrrole The preparation of this pyrrole bydecarboxylation of diethyl 2,4-dimethylpyrrole-3,5-dicarboxylate withhot sulfuric acid is described in the book: Die Chemie des Pyrrols, byH. Fischer and H. Orth (Leipzig 1934) vol. I, page 42. Using 200 g. ofthe ester they obtained 27 g. 2,4-dimethylpyrrole, a yield of 32% oftheory.

Running the decarboxylation with phosphoric acid we have heated 195 g.ester with 1 liter 85 phosphoric acid with stirring in a nitrogenatmosphere. Decarboxylation began slowly at 80 but due to the highmelting point of the ester the reaction proceeded rapidly only at -115and was finished in 30 minutes. After pouring the solution on 3 kg. ice,neutralization with strong ammonia, ether extraction of the pyrrole,drying the ether solution with M SO and evaporation of the solvent, the2,4-dimethylpyrrole was distilled in vacuo B.'P. 12 mm 50. 51.3 g. wasobtained, a yield of 66% of theory.

EXAMPLE l0 3-methyl-4,5,6,7-tetrahydroindole Ethyl3-methyl-4,5,6,7-tetrahydroindole 2 carboxylate (100 grams) and 800 ml.of 85% phosphoric acid is heated and stirred under nitrogen at 65 to 80C. Decarboxylation is completed in 15 minutes. The mixture is cooled andpoured onto 2 kg. of ice, neutralized with concentrated aqueous ammonia,the aqueous mixture extracted with ether, the ether dried over magnesiumsulfate, filtered evaporated to yield 3methyl-4,5,6,7-tetrahydroindole.

In accordance with the above procedure, but starting with ethyl3-methyl-4,5-cyclopenteno-pyrrole-2-carboxylate, ethyl2-methyl-4,5-cyclopentenopyrrole-3 carboxylate and ethyl2-methyl-4,5-cyclohepteno-pyrrole-3-carboxylate in place of ethyl3-methyl-4,5,6,7-tetrahydroindol-2 carboxylate, there is obtained thecorresponding 3-methyl- 4,S-cyclopenteno-pyrrole, Z-methyl 4,5cyclopentenopyrrole and 2-methyl-4,S-cyclohepteno-pyrrole.

EXAMPLE l1 2,3,5-trimethylpyrrole 2,4,5-trimethylpyrrol-3-yl methylketone (62 g.) was dissolved with stirring in 600 mml. of 85% H PO andheated in a nitrogen atmosphere to 140 for 30 minutes. After cooling to60 the solution was poured onto ice, neutralized with aqueous ammoniaand the pyrrole extracted with four portions of 200 ml. ether. Thecombined ether solutions were dried over magnesium sulfate, the solventevaporated, the residue distilled in vacuo yield 34 g.2,3,5-trimethylpyrrole (76% of theory) B.P. 74-76.

EXAMPLE 12 3-butyl-2,5-dimethylpyrrole 4-butyl-2,5-dimethylpyrrole-3-ylmethyl ketone 62 g.) was heated in 600 ml. 85% H PO for 30 minutes tounder nitrogen and worked up as described in the preceding example.There was obtained 40 g. 3-butyl-2,5- dimethylpyrrole (83% of theory)B.P. 102-106.

It will be understood that the foregoing description of the inventionand examples set forth, are merely illustrative of the principlesthereof. Accordingly, the appended claims are to be construed asdefining the invention within the full spirit and scope thereof.

We claim:

1. A method of preparing a C-substituted pyrrole of the followingFormula A R4R3 til. H

wherein R R R and R may each be hydrogen, lower alkyl having from 1 to 6carbon atoms, lower alkenyl having from 2 to 6 carbon atoms, cycloalkylhaving from 4 to 8 carbon atoms, phenyl, halophenyl, lower alkoxyphenylhaving from 1 to 6 carbon atoms, and benzyl, and R and R mayadditionally be linked together to form an alicyclic ring having from 5to 7 carbon atoms, provided that when Formula A is monocyclic, one ortwo members of the Group R R R and R are hydrogen, and when Formula A isbicyclic R or R is hydrogen,

which comprises heating a carbonyl compound of the following Formula Bwith phosphoric acid:

- Rall i I N R2 H Formula A Formula B wherein R R R and R may each beselected from the same groups from which R R R and R are selected, andin which one or two non-adjacent moieties selected from the groupconsisting of R R R and R are i C-R wherein R is R or OR in which R isalkyl having from 1 to 4 carbon atoms, phenyl or benzyl; neutralizingthe reaction mixture; and isolating the pyrrole of the foregoing FormulaA therefrom.

2. Method of claim 1, wherein the phosphoric acid has a concentration ofto 3. Method of claim 1, wherein the carbonyl compound is ethyl5-butyl-2,4-dimethylpyrrol-3-carboxylate.

4. Method of claim 1, wherein the carbonyl compound is ethylS-ethyl-2,4-dimethylpyrrole-3-carboxylate.

5. Method of claim 1, wherein the carbonyl compound is ethyl4-butyl-2,5-dimethylpyrrole-3-carboxylate.

6. Method of claim 1, wherein the carbonyl compound is methyl2-benzyl-4,5-dimethylpyrrole-3-carboxylate.

7. Method of claim 1, wherein the carbonyl compound is propylS-propyl-2,4-dimethylpyrrole-3-carboxylate.

8. Method of claim 1, wherein the carbonyl compound is ethyl2,4-dimethyl-5-phenylpyrrole-3-carboxylate.

9. Method of claim 1, wherein the carbonyl compound is diethyl2,4-dimethylpyrrole-3,S-dicarboxylate.

10, Method of claim 1, wherein the carbonyl compound is methyl2,4,5-trimethylpyrrol-3-yl ketone.

11. Method of claim 1, wherein the carbonyl compound is4-butyl-2,5-dimethylpyrrol-3-yl methyl ketone.

12. The method of claim 1, wherein the decarbonylation is carried out attemperatures of from 55 to 145 C.

13. The method of claim 1, wherein the carbonyl compound of Formula A isan ester and in which the resulting decarboxylation is carried out attemperatures of from 55 to C.

14. The method of claim 1, wherein the carbonyl compound of Formula A isa ketone and in which the resulting decarbonylation is carried out attemperatures of from to C.

References Cited UNITED STATES PATENTS 3,428,648 2/1969 Umio et al260-3131 ALEX MAZEL, Primary Examiner I. A. NARCAVAGE, AssistantExaminer US. Cl. X.R. 260319.1, 326.5

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, Datedl6.

Inventor(s) Karl sChOen t a1 It is certified that error appears in theabove-identified paten and that said Letters Patent are hereby correctedas shown below: Column 1, line 29, "decarbonylation" should read decarbm1 i Column 1, line 16, for "carbonyla'ting" rea carbonylation line 9,for "esters of ketones" read esters or ketones Colum line 50, for "they"read there Column 3, line 55 for "and" r an line 55, for "keetone" readketone line 68, for the dicarboxylic acid (XI) ester" read which resultsin the formati the dloarboxylic acid ester (XI) Column line 1, after"schemes read R, Column 5, line 63, for "soil" read oil Colu line 45,for "cyclopenteno-pyrrole" read cyclopentenopyrrole 1 for"cyclohepteno-pyrrole" read cycloheptenopyrrole line 50, f"cyclopenteno-pyrrole" read cyclopentenopyrrole line 51, for"cyclohepteno-pyrrole" read cycloheptenopyrrole Signed and sealed this7th day of September 1971 (SEAL) Attest:

EDWARD M.FLET 3 ROBERT GOTTSCHALK Attesting Officer Acting Commissionerof Pa

